title: The involvement of endoplasmic reticulum stress in the suppression of colorectal tumorigenesis by tolfenamic acid.
abstract: The nonsteroidal anti-inflammatory drug tolfenamic acid has been shown to suppress cancer cell growth and tumorigenesis in different cancer models. However, the underlying mechanism by which tolfenamic acid exerts its antitumorigenic effect remains unclear. Previous data from our group and others indicate that tolfenamic acid alters expression of apoptosis- and cell-cycle arrest-related genes in colorectal cancer cells. Here, we show that tolfenamic acid markedly reduced the number of polyps and tumor load in APC(min)(/+) mice, accompanied with cyclin D1 downregulation in vitro and in vivo. Mechanistically, tolfenamic acid promotes endoplasmic reticulum (ER) stress, resulting in activation of the unfolded protein response (UPR) signaling pathway, of which PERK-mediated phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) induces the repression of cyclin D1 translation. Moreover, the PERK-eIF2α-ATF4 branch of the UPR pathway plays a role in tolfenamic acid-induced apoptosis in colorectal cancer cells, as silencing ATF4 attenuates tolfenamic acid-induced apoptosis. Taken together, these results suggest ER stress is involved in tolfenamic acid-induced inhibition of colorectal cancer cell growth, which could contribute to antitumorigenesis in a mouse model.
authors.affiliation: College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996-4542. Phone: 865-974-8216; Fax: 865-974-5616; sbaek2@utk.edu; Qingwang Li, College of Animal Science and Technology, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi 712100, People's Republic of China. liqingwangysu@aliyun.com.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhang
authors.forename: Seong-Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Kyung-Won
authors.initials: KW
authors.lastname: Min
authors.forename: Michael F
authors.initials: MF
authors.lastname: McEntee
authors.forename: Jin Boo
authors.initials: JB
authors.lastname: Jeong
authors.forename: Qingwang
authors.initials: Q
authors.lastname: Li
authors.forename: Seung Joon
authors.initials: SJ
authors.lastname: Baek
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D025601:Adenomatous Polyposis Coli Protein / Q000502:physiology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003111:Colonic Polyps / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D056811:Unfolded Protein Response / Q000187:drug effects; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
chemical_list: D051701:Activating Transcription Factor 4; D025601:Adenomatous Polyposis Coli Protein; D000894:Anti-Inflammatory Agents, Non-Steroidal; D019938:Cyclin D1; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D019892:eIF-2 Kinase; D062367:ortho-Aminobenzoates; C081452:Atf4 protein, mouse; C009500:tolfenamic acid; C531557:eIF2alpha kinase, mouse